Lyn信号伝達における高親和性B細胞選択の分子信号

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 22021036
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kumamoto University
• Principal Investigator: 阪口 薫雄 熊本大学, 大学院・生命科学研究部, 教授 (70192086)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥8,800,000 (Direct Cost: ¥8,800,000); Fiscal Year 2011: ¥4,400,000 (Direct Cost: ¥4,400,000); Fiscal Year 2010: ¥4,400,000 (Direct Cost: ¥4,400,000)
• Keywords: 免疫学 / 生体分子 / 細胞・組織 / 感染症 / 遺伝子

Research Abstract

抗原特異的な高親和性B細胞産生には、(1)抗原特異的B細胞が増殖する胚中心の形成、(2)体細胞突然変異によるIgV領域遺伝子の変化、(3)高親和性B細胞の選択的増殖、が必要である。Src型チロシンキナーゼLynの標的として胚中心B細胞でAIDと結合してIgV領域DNAへのリクルートに関与するGANPが見つかっている。このGANPをLyn欠損マウスに発現誘導すると高親和性B細胞産生を起こすことができる。本研究ではLynを介するBCR信号のどの経路が高親和性B細胞の選択と増殖・分化誘導に必要なのか、そのメカニズムをDNA修復の観点から明らかにすることを目的とした。Lyn欠損ではhyperIgM免疫不全と共に抗DNA抗体をはじめ腎炎を発症する自己免疫疾患発症素因を有する。野生型B細胞は免疫後BCR,CD40等の共刺激を受けて抗原特異的なB細胞増殖を行い末梢リンパ組織にGCを形成する。T細胞依存性抗原NP-CGG免疫後、AID発現によってIgV領域にSHMが誘導され、高親和性B細胞が選択される。一方、Lyn欠損マウスは抗原免疫によってAID発現がおこりSHMの導入も存在するが、B細胞が増殖できない、あるいは生存が維持できずGCの形成がなく、その結果高親和性B細胞が生まれてこない。そこで、Lyn欠損マウスとGANP-Tgマウスを交配し、Lyn^<-/->GANP^<Tg>マウスを作製したところ、Lyn欠損GANP^<Tg>では抗原免疫によって、AID発現し、SHMが導入されIgV_H186.2の高親和性変異(W33→L)を持つB細胞が出現した。Lyn^<-/->GANP^<Tg>マウスのB細胞においてLyn信号伝達における高親和性B細胞選択に関わるポジティブ選別が改善される。一方、自己抗体産生細胞の出現は改善されないことからネガティブ選別にはLynを介する異なった経路によって実行されることが示唆された。これらの結果はGANPが抗原レセプター信号でLynを介する経路の高親和性B細胞誘導と選別の獲得免疫応答を担うことを証明したものである。

Research Products

• [Journal Article] Dynamic appearance of antigenic epitopes effective for viral neutralization during membrane fusion initiated by interactions between HIV-1 envelope proteins and CD4/CXCR4 (2012)
  • Author(s): Toda T, et al
  • Journal Title: Immunobiology Volume: (印刷中) Issue: 9 Pages: 864-872
  • DOI: 10.1016/j.imbio.2011.12.007
  • Peer Reviewed
• [Journal Article] Selective cell death of p53-insufficient cancer cells is induced by knockdown of the mRNA export molecule GANP (2012)
  • Author(s): Phimsen S, et al
  • Journal Title: Apoptosis Volume: (印刷中) Issue: 7 Pages: 679-690
  • DOI: 10.1007/s10495-012-0711-8
  • Peer Reviewed
• [Journal Article] Molecular Mechanism of Immunoglobulin V-Region Diversification Regulated by Transcription and RNA Metabolism in Antigen-Driven B Cells (2011)
  • Author(s): Sakaguchi N, et al
  • Journal Title: Scandinavian Journal of Immunology Volume: 73 Issue: 6 Pages: 520-526
  • DOI: 10.1111/j.1365-3083.2011.02557.x
  • Peer Reviewed
• [Journal Article] A novel serum carbohydrate marker on mucin 5AC : values for diagnostic and prognostic indicators for cholangiocarcinoma (2011)
  • Author(s): Silsirivanit A, et al
  • Journal Title: Cancer Volume: 117 Issue: 15 Pages: 3393-3403
  • DOI: 10.1002/cncr.25912
  • Peer Reviewed
• [Journal Article] Molecular Mechanism of Immunoglobulin V-Region Diversification Regulated by Transcription and RNA Metabolism in Antigen-Driven B Cells (2011)
  • Author(s): Sakaguchi N
  • Journal Title: Scandinavian Journal of Immunology Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] GANP-mediated recruitment of activation-induced cytidine deaminase to cell nuclei and to immunoglobulin variable region DNA (2010)
  • Author(s): Maeda K
  • Journal Title: Journal of Biological Chemistry Volume: 285 Pages: 23945-23953
  • Peer Reviewed
• [Journal Article] Critical role of Pcid2 in B cell survival through the regulation of MAD2 expression (2010)
  • Author(s): Nakaya T
  • Journal Title: Journal of Immunology Volume: 185 Pages: 5180-5187
  • Peer Reviewed
• [Presentation] GANP associated with HIV-1 RNA export is encapsidated with APOBEC3G into virion core (2012)
  • Author(s): Maeda K
  • Organizer: Keystone Symposia Mutations, Malignancy and Memory-Antibodies and Immunity
  • Place of Presentation: Boston Park Plaza & Towers
  • Year and Date: 2012-03-20
• [Presentation] Role of GANP in transcriptional regulation of immunoglobulin gene locus (2012)
  • Author(s): Sakaguchi N
  • Organizer: Keystone Symposia Mutations, Malignancy and Memory-Antibodies and Immunity
  • Place of Presentation: Boston Park Plaza & Towers
  • Year and Date: 2012-03-20
• [Presentation] Monoclonal antibodies (mAbs) against membrane fusion on HIV envelope-fusion complex (FC) enhanced appearance of neutralization target (2012)
  • Author(s): Toda T
  • Organizer: 新興・再興感染症に関するアジアリサーチフォーラム-2012
  • Place of Presentation: 神戸国際会議場・兵庫
  • Year and Date: 2012-01-10
• [Presentation] APOBEC3GのHIV-1粒子内への取り込みを制御する宿主因子GANP (2011)
  • Author(s): 前田和彦
  • Organizer: 第25回日本エイズ学会学術集会
  • Place of Presentation: ハイアットリージェンシー東京
  • Year and Date: 2011-12-01
• [Presentation] HIV-1 gp120/CD4&CXCR4膜融合複合体エピトープと感染阻止効果 (2011)
  • Author(s): 戸田哲平
  • Organizer: 第25回日本エイズ学会学術集会
  • Place of Presentation: ハイアットリージェンシー東京
  • Year and Date: 2011-11-30
• [Presentation] 広範な中和活性を有する抗体エピトープの同定を目的としたHIV env-CD4膜融合複合体に対するモノクローナル抗体の開発 (2011)
  • Author(s): 戸田哲平
  • Organizer: The 40th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-28
• [Presentation] GANP is required for prevention of DNA damage and cell apoptosis (2011)
  • Author(s): Phimsen S
  • Organizer: The 40th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-28
• [Presentation] Analysis of GANP-associated complex in B-cell nuclei (2011)
  • Author(s): Maeda K
  • Organizer: The 40th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-28
• [Presentation] Involvement of GANP in transcriptional regulation of immunoglobulin gene locus (2011)
  • Author(s): Singh SK
  • Organizer: The 40th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-28
• [Presentation] GANP augments the immunoglobulin Vregion gene conversion via Ku70 dependent mechanism (2011)
  • Author(s): Eid MMA
  • Organizer: The 40th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-28
• [Presentation] Lynを介するシグナルターゲットであるGANPは末梢リンパ組織における高親和性抗体産生B細胞の維持に重要である (2011)
  • Author(s): 桑原一彦
  • Organizer: The 40th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-27
• [Presentation] An apoptotic regulator G5PR is highly expressed in centrocytes and critical for B cell survival in mice (2011)
  • Author(s): Kitabatake M
  • Organizer: The 40th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-26
• [Presentation] GANP promotes APOBEC3G encapsidation in virions to reduce viral infectivity (2011)
  • Author(s): Maeda K
  • Organizer: The 12th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko Kumamoto, Aso Resort Grandvrio Hotel
  • Year and Date: 2011-10-21
• [Presentation] Dynamic changes in antigenic memberane fusion epitopes initiated by interactions between HIV-1 envelope proteins and CD4/CXCR4 (2011)
  • Author(s): Toda T
  • Organizer: The 12th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko Kumamoto, Aso Resort Grandvrio Hotel
  • Year and Date: 2011-10-20
• [Presentation] Glycans in MUC5AC mucin as diagnostic/prognostic and early markers for cholangiocarcinoma (2011)
  • Author(s): Wongkham S
  • Organizer: 日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場・愛知
  • Year and Date: 2011-10-04
• [Presentation] 乳腺特異的GANP欠損マウスにおける乳管形成障害と相関する高頻度乳癌発症 (2011)
  • Author(s): 桑原一彦
  • Organizer: 日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場・愛知
  • Year and Date: 2011-10-04
• [Presentation] 高親和性単クローン抗体による胆管癌特異的糖鎖エピトープの同定 (2011)
  • Author(s): 阪口薫雄
  • Organizer: 日本がん免疫学会
  • Place of Presentation: 千里ライフサイエンスセンター大阪
  • Year and Date: 2011-07-01
• [Presentation] 乳腺特異的GANP欠損マウスにおける乳癌発症機構の解析 (2011)
  • Author(s): 桑原一彦
  • Organizer: 日本がん分子標的治療学会
  • Place of Presentation: ホテル日航東京
  • Year and Date: 2011-06-24
• [Presentation] RNA metabolism and antibody affinity maturation (2011)
  • Author(s): Sakaguchi N
  • Organizer: Immunology Symposium Basel (ISB) 2011 on "Immune Responses and Autoimmunity"
  • Place of Presentation: University of Basel
  • Year and Date: 2011-06-10
• [Presentation] GANP associated with HIV-1 RNA export is encapsidated with Apobec3G into virion cores (2011)
  • Author(s): Maeda K
  • Organizer: The 2011 Meeting on Retroviruses at Cold Spring Harbor Laboratory
  • Place of Presentation: Cold Spring Harbor, New York
  • Year and Date: 2011-05-25
• [Presentation] Transcriptional targeting at immunoglobulin V-region locus by an RNA-export molecule GANP (2011)
  • Author(s): 前田和彦
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: KKRホテル熊本、熊本
  • Year and Date: 2011-05-20
• [Presentation] Regulation of immune function by controlling RNA metabolism. The 2nd Workshop of Synthetic Immunology (2010)
  • Author(s): Sakaguchi N
  • Organizer: The 2nd Workshop of Synthetic Immunology
  • Place of Presentation: Kyoto University Shiran Kaikan, Inamori Hall
  • Year and Date: 2010-12-17
• [Presentation] Apobec3GのHIV-1粒子内への取り込みを制御する宿主因子の同定 (2010)
  • Author(s): 阪口薫雄
  • Organizer: 第24回日本エイズ学会学術集会
  • Place of Presentation: グランドプリンスホテル高輪/ザ・プリンスさくらタワー東京
  • Year and Date: 2010-11-24
• [Presentation] GANP is a host factor that regulates Apobec3G encapsidation to HIV-1 viruses (2010)
  • Author(s): Sakaguchi N
  • Organizer: Asian-African Research Forum 2010
  • Place of Presentation: Hanoi ベトナムホテルメリアハノイ
  • Year and Date: 2010-11-01
• [Presentation] GANP-mediated recruitment of AID to the nuclei and to IgV-region DNA (2010)
  • Author(s): Maeda K
  • Organizer: The 5th International Conference on Gene Regulation in Lymphocyte Development Aegean Conferences
  • Place of Presentation: Minoa Palace Conference. Center Greece ギリシャ
  • Year and Date: 2010-10-09
• [Presentation] GANP regulates the incorporation of Apobec3G into HIV-1 virions (2010)
  • Author(s): Maeda K
  • Organizer: The 11th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko Kumamoto, Aso Resort Grandvrio Hotel
  • Year and Date: 2010-10-06
• [Presentation] GANP controls AID recruitment to immunoglobulin variable region DNA (2010)
  • Author(s): Maeda K
  • Organizer: The 14th International Congress of Immunology
  • Place of Presentation: The Kobe Convention Center Complex
  • Year and Date: 2010-08-22
• [Presentation] A role of chromatin modification at immunoglobulin locus by GANP (2010)
  • Author(s): Singh SK
  • Organizer: The 14th International Congress of Immunology
  • Place of Presentation: The Kobe Convention Center Complex
  • Year and Date: 2010-08-22
• [Presentation] Over-expression of protein phosphatase subunit G5PR that suppresses JNK-mediated apoptosis caused the increase of B-1 cells associated with autoimmunity (2010)
  • Author(s): Kitabatake M
  • Organizer: The 14th International Congress of Immunology
  • Place of Presentation: The Kobe Convention Center Complex
  • Year and Date: 2010-08-22
• [Presentation] GANP plays a critical role in activation of B cell proliferation as a Lyn-mediated signaling target (2010)
  • Author(s): Nakaya T
  • Organizer: The 14th International Congress of Immunology
  • Place of Presentation: The Kobe Convention Center Complex
  • Year and Date: 2010-08-22
• [Presentation] Mammalian GANP and Thp1/Pcid2 are associated and coordinately involved in B cell proliferation (2010)
  • Author(s): Kuwahara K
  • Organizer: The 14th International Congress of Immunology
  • Place of Presentation: The Kobe Convention Center Complex
  • Year and Date: 2010-08-22
• [Presentation] Role of GANP in cell-cycle progression (2010)
  • Author(s): Phimsen S
  • Organizer: The 14th International Congress of Immunology
  • Place of Presentation: The Kobe Convention Center Complex
  • Year and Date: 2010-08-22
• [Presentation] Newly established anti-CD4 antibody affects HIV-1 infection (2010)
  • Author(s): Toda T
  • Organizer: The 14th International Congress of Immunology
  • Place of Presentation: The Kobe Convention Center Complex
  • Year and Date: 2010-08-22
• [Presentation] Molecular mechanism of immunoglobulin V-region diversification and its application in medical sciences (2010)
  • Author(s): 阪口薫雄
  • Organizer: 日本ヒトプロテオーム機構第8回大会(日本プロテオーム学会2010年会)・第6回日本臨床プロテオーム研究会・連合大会
  • Place of Presentation: 東京ベイホテル東急
  • Year and Date: 2010-07-26
• [Book] プロテインホスファターゼ2Aの調節と自己免疫 (2012)
  • Author(s): 前田和彦, 他
  • Publisher: 科学評論社
• [Book] 自己免疫疾患とB1細胞 (2012)
  • Author(s): 北畠正大, 他
  • Publisher: 科学評論社
• [Book] 高親和性抗体産生のメカニズム (2011)
  • Author(s): 前田和彦, 他
  • Publisher: 羊土社
• [Book] 胚中心B細胞の分化・増殖とGANP (2011)
  • Author(s): 前田和彦, 他
  • Publisher: 科学評論社
• [Book] 加齢とreceptor editing機能 (2011)
  • Author(s): 戸田哲平, 阪口薫雄
  • Publisher: 科学評論社
• [Book] 抗体の抗原親和性成熟とGANPの役割 (2010)
  • Author(s): 前田和彦, 阪口薫雄
  • Publisher: 科学評論社
• [Book] B細胞のreceptor editingと自己免疫疾患 (2010)
  • Author(s): 戸田哲平, 阪口薫雄
  • Publisher: 科学評論社
• [Book] 第6章翻訳 (2010)
  • Author(s): 阪口薫雄
  • Publisher: メディカル・サイエンス・インターナショナル
• [Remarks]
  • URL: http://www.k-immu.jp/ja/index.html
• [Remarks]
  • URL: http://www.k-immu.jp/ja/index.html